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© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Sleep loss has been associated with increased seizure risk since antiquity. Using automated video detection of spontaneous seizures in Drosophila epilepsy models, we show that seizures worsen only when sleep restriction raises homeostatic “sleep drive,” not simply when total sleep amount falls. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep drive without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleep drive protects against seizures. Downregulation of the 5HT1A serotonin receptor in sleep-promoting cells mediates the effect of sleep drive on seizures, and we identify an FDA-approved 5HT1A agonist to mitigate seizures. Our findings demonstrate that while homeostatic sleep is needed to recoup lost sleep, sleep drive comes at the cost of increasing seizure susceptibility.

Sleep loss has been known to increase seizure risk since antiquity, but the underlying mechanisms remain unclear. Using fruit-fly epilepsy models, the authors show that rising “sleep drive”, not sleep duration, is what triggers seizures.

Details

Title
Sleep drive, not total sleep amount, increases seizure risk
Author
Cuddapah, Vishnu Anand 1   VIAFID ORCID Logo  ; Hsu, Cynthia T. 2 ; Valle Sirias, Fernanda 1 ; Li, Yongjun 3   VIAFID ORCID Logo  ; Shah, Hrishit M. 3 ; Saul, Christopher 4 ; Killiany, Samantha 3 ; Guevara, Camilo 3   VIAFID ORCID Logo  ; Shon, Joy 3 ; Yue, Zhifeng 3 ; Gionet, Gabrielle L. 5 ; Putt, Mary E. 5   VIAFID ORCID Logo  ; Sehgal, Amita 3   VIAFID ORCID Logo 

 Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA (ROR: https://ror.org/05cz92x43) (GRID: grid.416975.8) (ISNI: 0000 0001 2200 2638); Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA (ROR: https://ror.org/02pttbw34) (GRID: grid.39382.33) (ISNI: 0000 0001 2160 926X) 
 Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, USA (ROR: https://ror.org/00b30xv10) (GRID: grid.25879.31) (ISNI: 0000 0004 1936 8972); Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA (ROR: https://ror.org/00b30xv10) (GRID: grid.25879.31) (ISNI: 0000 0004 1936 8972); Department of Biology, California State University Fresno, Fresno, CA, USA (ROR: https://ror.org/03enmdz06) (GRID: grid.253558.c) (ISNI: 0000 0001 2309 3092) 
 Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, USA (ROR: https://ror.org/00b30xv10) (GRID: grid.25879.31) (ISNI: 0000 0004 1936 8972); Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA (ROR: https://ror.org/00b30xv10) (GRID: grid.25879.31) (ISNI: 0000 0004 1936 8972) 
 Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, USA (ROR: https://ror.org/00b30xv10) (GRID: grid.25879.31) (ISNI: 0000 0004 1936 8972); Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA (ROR: https://ror.org/00b30xv10) (GRID: grid.25879.31) (ISNI: 0000 0004 1936 8972); Department of Chemical & Biomolecular Engineering, University of Delaware, Newark, DE, USA (ROR: https://ror.org/01sbq1a82) (GRID: grid.33489.35) (ISNI: 0000 0001 0454 4791) 
 Department of Biostatistics, Epidemiology and Informatics University of Pennsylvania, Philadelphia, PA, USA (ROR: https://ror.org/00b30xv10) (GRID: grid.25879.31) (ISNI: 0000 0004 1936 8972); CHOP/Penn Intellectual and Developmental Disabilities Research Center, Philadelphia, PA, USA (ROR: https://ror.org/01z7r7q48) (GRID: grid.239552.a) (ISNI: 0000 0001 0680 8770) 
Pages
6967
Section
Article
Publication year
2025
Publication date
2025
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3234541845
Copyright
© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.